X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases

BRIEF REVIEW www.jasn.org X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases Barbara R. Migeon McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University, Baltimore Maryland ABSTRACT A good deal of sex differences in kidney disease is attributable to sex differences expressed only in the testes, they have to do in the function of genes on the X chromosome. Males are uniquely vulnerable to with testicular function and fertility. With mutations in their single copy of X-linked genes, whereas females are often mosaic, one X chromosome, males have only a sin- having a mixture of cells expressing different sets of X-linked genes. This cellular gle copy of their X-linked genes. mosaicism created by X inactivation in females is most often advantageous, pro- On the other hand, even though fe- tecting carriers of X-linked mutations from the severe clinical manifestations seen males have two copies of these genes, in males. Even subtle differences in expression of many of the 1100 X-linked genes both are not expressed in the same cell. may contribute to sex differences in the clinical expression of renal diseases. Only one X is programmed to work in each diploid somatic cell. All of the other J Am Soc Nephrol 19: 2052–2059, 2008. doi: 10.1681/ASN.2008020198 X chromosomes in the cell become inactive during fetal development. Briefly, compensation for X dosage in our spe- Although being female conveys a protec- with normal kidney function. This re- cies is accomplished by a process that en- tive effect on the progression of chronic view addresses the genetic and epigenetic sures only a single X is active in both renal disease, the basis for this sex differ- programs that contribute to the sex dif- sexes. In cells with more than two X ence is not well understood. Little is ferences in renal diseases. chromosomes, all X chromosomes but known about the effects of sex on the de- Without doubt, the clinical manifes- one are silenced. velopment of the kidney. The numbers tations of renal diseases are influenced by In human females, the choice of the of glomeruli are the same for men and X inactivation, the developmental pro- active X chromosome is random so that women, and the greater glomerular vol- gram that equalizes the transcriptional the X inherited from the father has the ume in males is related to the larger size output of X–linked genes in males and same possibility of being active as the X of their kidneys and body surface area.1 females.4 X inactivation is an obligatory inherited from the mother. Silencing of In the absence of structural differences to program, driven by the sex difference in the other X or Xs is mediated by the syn- account for the accelerated progression the numbers of X chromosomes that thesis of a special type of noncoding RNA of renal injury in males, hormonal differ- arose during mammalian evolution. The molecule emanating from the X inactive ences have been implicated. Animal human Y chromosome was created by transcript (XIST) locus on the X chromo- models support the protective effect of destroying one member of the chromosome.6 Spreading along the chromosome, estrogen on glomerulonephritis and the some pair that evolved into our sex chro- these molecules modify the underlying nephrotoxic effects of testosterone,2 yet a mosomes. As a result, XX females have chromosome and induce transcriptional great deal of evidence implicates events two X chromosomes, whereas XY males silence. Once silenced, most genes on the occurring during embryonic develop- have only one. The DNA sequence of the ment. The effect of poor nutrition and human X chromosome reveals about other maternal factors leading to low 1100 genes, an eclectic group, encoding Published online ahead of print. Publication date birth weight can reduce the numbers of proteins needed for almost all of our available at www.jasn.org. nephrons in the developing kidney,3 but body functions, some having to do with Correspondence: Dr. Barbara R. Migeon, McKu- the effect is the same for males and fe- sex but most involving nonsexual activi- sick-Nathans Institute of Genetic Medicine, 459 5 Broadway Research Building, 733 N. Broadway, Bal- males. What is generally ignored in any ties. In contrast, the genes on the Y chro- timore, MD 21205. Phone: 410-955-3049; Fax: 410- discussion of sex differences in renal dis- mosome are far less diverse. Although a 614-8600; E-mail: [email protected] ease are the relevant genes on the X chro- few share functions with their X-linked Copyright ᮊ 2008 by the American Society of mosome, which when mutated interfere counterpart, most are unique to the Y; Nephrology 2052 ISSN : 1046-6673/1911-2052 J Am Soc Nephrol 19: 2052–2059, 2008 www.jasn.org BRIEF REVIEW inactive X usually remain mute in all when one of the X-linked alleles is mutant ized regions of the ureteric bud by small daughter cells, so that the inactivation pat- and the other is normal. However, in fact, groups of cells that communicate with ad- tern is clonally inherited.7 the comingling of cells synthesizing differ- jacent groups of cells, all of this under the As a consequence of clonal inheritance ent X-linked proteins, whether normal or control of a variety of transcription and of the inactive X, human females are mo- abnormal proteins, is responsible for a other signaling factors. And the develop- saics, a composite of two populations of functional diversity not seen with most au- ment of glomeruli requires interactions be- cells that differ as to which X chromosome tosomal genes. Males with only a single tween epithelial cells and infiltrating endo- is expressed. This mosaicism would be copy of their X-linked genes are at a disad- thelial cells. What is not known is the meaningless if the alleles on maternal and vantage as they have less diversity and are nature of the sex differences in this process. paternal X chromosomes were identical as vulnerable to the effects of mutations at a There are bound to be sex differences be- they are in inbred laboratory mice; how- large number of loci, including those cause of the cellular mosaicism resulting ever, we, as a species, are so heterozygous shown in Table 1. It is this cellular mosa- from X inactivation. Also not known is the that females are indeed mosaic for a good icism that provides biologic advantage to mosaic composition of the kidney. Do the number of their X-linked alleles. The size females carrying mutations responsible for different cells that communicate to induce of the mosaic patch differs from tissue to kidney disease in males. the kidney express the same or different pa- tissue.8 It is very large in the placenta where rental X chromosomes? The onset of X in- all of the cells within a chorionic villus have Sex Differences in Renal activation is timed with the differentiation the same active X, and very small in the Development events that give rise to the various tis- brain with a great deal of comingling of the The development of the kidney is intricate sues11,12; therefore, in the kidney, it might two types of cells. The phenotype of any cell because of its architectural complexity. coincide with the earliest events in renal is determined not only by the allele it ex- The entire urinary collecting system starts differentiation. Clearly, the time when X presses, but also by the interactions with as an outgrowth of the Wolffian duct and inactivation occurs precedes the time when those neighbors, expressing the other al- forms by a complex process of branching the kidney is completely formed in hu- lele. Such interactions are best seen and remodeling.9,10 According to Costan- mans. From what is known about develop- through the window of disease, that is, tini,10 branching may be initiated in local- ment of the mouse kidney, most nephro- Table 1. Sex differences in renal manifestations of X-linked diseases affecting the kidney Mutated Male Renal Disease OMIM# X Mapa Female Renal Phenotypeb Gene Phenotypeb Alport syndrome 301050 Xq22.3 COL4A5 Nephritis; glomerulitis; Some hematuria; rarely ESRD Leiomyomatosis with 308940 Xq22.3 COL4A5 & hematuria; ESRD nephropathologyc COL4A6 Dent disease 1 300009 Xp11.22 CLCN5 Progressive proximal tubular Usually asymptomatic; Nephrolithiasis 310468 Xp11.22 CLCN5 disease; ESRD; hypercalciuria; occasionally proteinuria and Hypophosphatemic rickets 300554 Xp11.22 CLCN5 nephrolithiasis; proteinuria; hypercalcinuria recessive hypophosphatemic rickets Low molecular weight 308990 Xp11.22 CLCN5 proteinuria Dent disease 2 300555 Xq26.1 OCRL Proteinuria; aminoaciduria; Usually asymptomatic; some Lowe’s syndrome 309000 Xq26.1 OCRL phosphaturia aminoaciduria Fabry disease 301500 Xq22 GLA Cytoplasmic inclusions, Less severe inclusions; proteinuria, ESRD occasionally ESRD Hypophosphatemic rickets 307800 Xp22.1–2 PHEX Hypophosphatemia; More variable and less severe dominant (vitamin D nephrocalcinosis resistant) Lesch-Nyhan syndrome 300322 Xq26–27.2 HPRT Uric acid stones, nephropathy, Usually none and renal obstruction Nephrogenic diabetes 304800 Xq28 AVPR2Ϫ Excessive diuresis Milder symptoms if any insipidus Syndrome of inappropriate 300539 Xq28 AVPR2ϩ Gain of function: hyponatremia, Variable, but usually less severe antidiuresis systolic hypertension Oral facial digital 311200 Xp22.2 OFD1 Fetal death Polycystic disease, ESRD syndrome 1 ESRD, End-stage renal disease. aLocation of the gene on the X chromosome. bHemizygous male and heterozygous female. cContiguous gene syndrome with large deletions. J Am Soc Nephrol 19: 2052–2059, 2008 Sex Differences in Renal Diseases 2053 BRIEF REVIEW www.jasn.org genic and glomerular development occurs cells. Usually, the distribution of the two bolic cooperation through gap junctions, after the onset of X inactivation.

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